The main objective in human immunodeficiency virus (HIV) therapy is the identification, targeting and elimination of viral reservoirs. While significant progress has been made in the field, the low levels of viral RNA detected in patients under antiretroviral therapy as well as the rebound of viral replication after cessation of such therapy suggest that there are additional HIV reservoirs present. Recent studies have suggested that hematopoietic stem/progenitor cells (HSPC) in the bone marrow can be infected by HIV and harbor latent virus. The goal of the proposed studies is to fully characterize HIV infection in the bone marrow in vivo and to assess the ways to target HIV infected progenitors. As stem cell based gene therapy is considered a potentially new avenue to eradicate HIV, it is essential to fully understand how this new reservoir impacts engraftment of and reconstitution by new stem cells. To address this question we aim to (i) fully characterize HIV infection in HSPC using both humanized mice and human tissues (fetal liver, cord blood) ex vivo, (ii) examine the effect HIV infection has on the bone marrow microenvironment and its ability to support proper lineage development in vivo, and (iii) evaluate gene therapy approaches to impact the viral reservoir, including the development of ways to protect genetically modified antiviral effector cells.